A variety of medical techniques have been used for imaging biological tissues and organs are known. These include traditional x-rays, ultra-sound, magnetic resonance imaging (MRI), and computerized tomography (CT). Techniques such as MRI, micro-CT, micro-positron emission tomography (PET), and single photon emission computed tomography (SPECT) have been explored for imaging function and processes in small animals or in vivo, intra operatively. These technologies offer deep tissue penetration and high spatial resolution, but are costly and time consuming to implement.
A variety of dyes useful for medical imaging have been described, including radio opaque dyes, fluorescent dyes, and calorimetric dyes (see e.g., U.S. Pat. Nos. 5,699,798; 5,279,298; 6,351,663). Imaging techniques and systems using fluorescent dyes have been described for some organs, such as the eye (see, e.g., U.S. Pat. No. 5,279,298) In the eye, some dyes can serve both an imaging function and a therapeutic function (see, e.g., U.S. Pat. No. 6,840,933). Non-toxic tracers such as Indocyanine Green (ICG), fast blue, and fluorogold, have been used in mammals without evidence of neuronal toxicity several months after the treatment (Thielert et al., J Comp Neurol. 337(1):113 (1993); Yeterian et al., Exp Brain Res. 99(3):383 (1994); vogt Weisenhorn et al., J Comp Neurol. 362(2):233 (1995)).
In one study for use of ICG in surgical procedures, nine patients undergoing surgery for the removal of intrinsic brain tumors with enhanced optical imaging was performed using ICG as an intravenous contrast-enhancement agent. Optical images were obtained before and after injection of the ICG. The patients in the study showed differences in the dynamic optical signals among normal brain, low-grade astrocytomas, and malignant astrocytomas. Optical imaging of the resection margins in malignant tumors showed differences between adjacent normal tissue and remaining tumor tissue. Haglund, M. et al., Enhanced optical imaging of human gliomas and tumor margins. Neurosurgery, 38(2):308-317 (1996).
Renal cortical malignancies are the seventh most commonly diagnosed cancer in the US. Approximately 36,160 new cases of renal cancers were diagnosed in 2005, (22,490 in men and 13,670 in women), and about 12,660 people (8020 men and 4640 women) died from this disease. These statistics include both adults and children with renal cell carcinomas, Wilms' tumors and transitional cell carcinomas of the renal pelvis. Eliminating upper urinary tract transitional cell carcinoma and childhood tumors from the number of all renal neoplasms, renal cortical tumors accounted for more than 31,500 new cases in 2005. Most people with renal cell cancer are at middle age with its peak incidence between the ages of 50 and 74. Mortality, accounting for 3% of all cancer related deaths, has remained unchanged despite the increase in disease incidence. For reasons that are not completely clear, the kidney cancer rate has been increasing about 1.5% per year. This is likely due to incidental cancer detection during diagnostic procedures such as ultrasound and abdominal CT scans. With the increasing detection of incidental renal lesions, the evaluation and management of solid and cystic renal tumors are of even greater importance to physicians dealing with renal cell cancer.
Improved quality and readily available imaging has substantially increased the number of incidental renal tumors detected. Multiple studies showed that disease-free survival rates were similar between cancers treated with radical and partial nephrectomy. The surgical management of renal cell carcinoma has undergone significant changes over the past fifteen years. Initially treated with radical nephrectomy, most cases of renal cell carcinoma are now approached with nephron-sparing surgical technique irrespective of tumor size.
More recent issues regarding partial nephrectomy have been complication rates and their subsequent management, renal cell carcinoma multifocality, margin status, distance to normal renal parenchyma, cost analysis, and the development of minimally invasive techniques with similar success and complication rate as open partial nephrectomy. (Desai, M. et al., Laparoscopic partial nephrectomy versus laparoscopic cryoablation for the small renal tumor. Urology, 66(5 Suppl):23-28 (2005), Diblasio, C. et al., Mini-flank supra-11th rib incision for open partial or radical nephrectomy, BJU Int, 97(1):149-156 (2006), Gill, I. et al., Comparative analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients. J Urol, 170(1):64-68 (2003)). Newer and more technologically advanced techniques developed during the last 10 years to treat small cortical lesions include radiofrequency ablation (RFA), cryoablation, and high intensity focused ultrasound (HIFU). Currently, all of these procedures are being performed either percutaneously, laparoscopically or as a part of open procedure. (Weizer, A. et al., Complications after percutaneous radiofrequency ablation of renal tumors, Urology, 66(6):1176-1180 (2005), Ahrar, K. et al., Percutaneous radiofrequency ablation of renal tumors: technique, complications, and outcomes. J Vasc Interv Radiol, 16(5):679-688 (2005)).
Not all tumors amenable to partial nephrectomy are easily seen at surgery. Significant subsets of the tumors are located intracortically, intrarenally or in the renal hilar area. To better assess these tumors, intra operative ultrasound with or without needle localization has been developed to increase the negative margin rate while decreasing resection of normal renal tissue or necessitate the conversion to open radical nephrectomy. To date, there are no reported studies that have reviewed cancer control in patients undergoing renal sparing surgery with intra operative ultrasound. Similarly, multifocality of renal cortical tumors is well known and poses a difficult task for the urologic surgeon.
Multifocal tumor occurrence is a clear risk factor for cancer recurrence, progression of disease and the need for additional surgeries. Intra operative ultrasound is the only imaging modality used in assessment of small satellite lesions. Pre operatively, lesions that are 8-10 mm in size can be characterized using CT and MRI. Many times there will be small (<8 mm) lesions present that can not be visualized with current day CT and MRI scanners and are only noticed intra operatively. Unfortunately, in some cases unexpected intra operative findings of multifocal tumor lesions will preclude partial nephrectomy and necessitate conversion to radical nephrectomy. All these increase the risk of chronic renal insufficiency and possibly the need for dialysis. (McKieman, J. et al., Natural history of chronic renal insufficiency after partial and radical nephrectomy. Urology, 59(6): p. 816-820 (2002)). Nephron-sparing surgery provides effective therapy for patients with borderline renal insufficiency or in whom preservation of renal function is a critical clinical consideration.
Meticulous operative technique is of utmost importance for achieving acceptable oncologic and functional outcomes. To further improve partial nephrectomy results, intra operative imaging has been introduced, mainly using intra operative ultrasound. This method requires an experienced ultrasonographer and special equipment, and sometimes results in time consuming imaging without successful demonstration of clear margins. (Assimos, D. et al., Intraoperative renal ultrasonography: a useful adjunct to partial nephrectomy. J Urol, 146(5): p. 1218-1220 (1991)).
Despite its drawbacks, intra operative ultrasonography has proven valuable in delineating tumor extent and margins during nephron-sparing surgery and in evaluating the presence of synchronous multifocality. Several investigators have found intra operative ultrasound to be helpful in characterizing renal lesions. Findings on intra operative ultrasound have changed the intra operative approach in 17 to 33% of select patients planned for partial nephrectomy. The reported mean cancer specific survival of all patients undergoing nephron-sparing surgery for any indication is 72%-100%. In more recent studies, selection criteria were better defined and the disease specific survival rate exceeded 90%.
It would be desirable to have a less cumbersome technique that can be performed by all members of the surgical team and which can increase the opportunity to spare nephrons without compromising the ability to remove tumors. The present invention fills these and other needs.